tbuckley/cabot-search huggingface dataset:
Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis
Authors: Laura Martinez-Gili, Alexandros Pechlivanis, Julie A.K. McDonald, Sofina Begum, Jonathan Badrock, Jessica K. Dyson, Rebecca Jones, Gideon Hirschfield, Stephen D. Ryder, Richard Sandford, Simon Rushbrook, Douglas Thorburn, Simon D. Taylor-Robinson, Mary M.E. Crossey, Julian R. Marchesi, George Mells, Elaine Holmes, David Jones
Journal: Gut Microbes (2023)

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.
Dietary protein shapes the profile and repertoire of intestinal CD4+ T cells
Authors: Ainsley Lockhart, Aubrey Reed, Tiago Rezende de Castro, Calvin Herman, Maria Cecilia Campos Canesso, Daniel Mucida
Journal: The Journal of Experimental Medicine (2023)

The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring CD4+ T cells. Combining antigenically defined diets with gnotobiotic models, we show that food and microbiota distinctly influence the profile and T cell receptor repertoire of intestinal CD4+ T cells. Independent of the microbiota, dietary proteins contributed to accumulation and clonal selection of antigen-experienced CD4+ T cells at the intestinal epithelium, imprinting a tissue-specialized transcriptional program including cytotoxic genes on both conventional and regulatory CD4+ T cells (Tregs). This steady state CD4+ T cell response to food was disrupted by inflammatory challenge, and protection against food allergy in this context was associated with Treg clonal expansion and decreased proinflammatory gene expression. Finally, we identified both steady-state epithelium-adapted CD4+ T cells and tolerance-induced Tregs that recognize dietary antigens, suggesting that both cell types may be critical for preventing inappropriate immune responses to food.
The US Health Equity Crisis—An Economic Case for a Moral Imperative?
Authors: Rishi K. Wadhera, Issa J. Dahabreh
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Estimated Rates of Incident and Persistent Chronic Pain Among US Adults, 2019-2020
Authors: Richard L. Nahin, Termeh Feinberg, Flavia P. Kapos, Gregory W. Terman
Journal: JAMA Network Open (2023)

Chronic pain risk and prognosis estimates are needed to inform effective interventions.To estimate rates of chronic pain and high-impact chronic pain (HICP) incidence and persistence in US adults across demographic groups.This cohort study examined a nationally representative cohort with 1 year of follow-up (mean [SD], 1.3 [0.3] years). Data from the 2019-2020 National Health Interview Survey (NHIS) Longitudinal Cohort were used to assess the incidence rates of chronic pain across demographic groups. The cohort was created using random cluster probability sampling of noninstitutionalized civilian US adults 18 years or older in 2019. Of 21 161 baseline participants in the 2019 NHIS who were randomly chosen for follow-up, 1746 were excluded due to proxy response(s) or lack of contact information, and 334 were deceased or institutionalized. Of the 19 081 remaining, the final analytic sample of 10 415 adults also participated in the 2020 NHIS. Data were analyzed from January 2022 to March 2023.Self-reported baseline sex, race, ethnicity, age, and college attainment.Primary outcomes were the incidence rates of chronic pain and HICP, and secondary outcomes were the demographic characteristics and rates across demographic groups. A validated measure of pain status ("In the past 3 months, how often did you have pain? Would you say never, some days, most days, or every day?") yielded 3 discrete categories each year: pain free, nonchronic pain, or chronic pain (pain "most days" or "every day"). Chronic pain present in both survey years was considered persistent; HICP was defined as chronic pain that limited life or work activities on most days or every day. Rates were reported per 1000 person-years (PY) of follow-up, and age standardized based on the 2010 US adult population.Among 10 415 participants included in the analytic sample, 51.7% (95% CI, 50.3%-53.1%) were female, 54.0% (95% CI, 52.4%-55.5%) were aged 18 to 49 years, 72.6% (95% CI, 70.7%-74.6%) were White, 84.5% (95% CI, 81.6%-85.3%) were non-Hispanic or non-Latino, and 70.5% (95% CI, 69.1%-71.9%) were not college graduates. Among pain-free adults in 2019, incidence rates of chronic pain and HICP in 2020 were 52.4 (95% CI, 44.9-59.9) and 12.0 (95% CI, 8.2-15.8) cases per 1000 PY, respectively. The rates of persistent chronic pain and persistent HICP in 2020 were 462.0 (95% CI, 439.7-484.3) and 361.2 (95% CI, 265.6-456.8) cases per 1000 PY, respectively.In this cohort study, the incidence of chronic pain was high compared with other chronic diseases. These results emphasize the high disease burden of chronic pain in the US adult population and the need for early management of pain before it becomes chronic.
Torsemide vs Furosemide After Discharge and All-Cause Mortality in Patients With Heart Failure—Reply
Authors: Robert J. Mentz, Tracy A. DeWald, Eric J. Velazquez
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Dual receptor T cells mediate effective antitumor immune responses via increased recognition of tumor antigens
Authors: Hyun J Jang, Christine Caron, Calvin K Lee, Lu Wang, Burhan Jama, Jack D Bui, Gerald P Morris
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Discovery that ~16% of T cells naturally co-express two T-cell receptor (TCR) clonotypes prompts examining the role of dual TCR cells in immune functions. Methods Using TCRα-reporter transgenic mice, enabling unambiguous identification of single-TCR and dual-TCR cells, we tested the role of dual TCR cells in antitumor immune responses against immune-responsive syngeneic 6727 sarcoma and immune-resistant B16F10 melanoma. Results Dual TCR cells were specifically increased among tumor-infiltrating lymphocytes (TILs) in both models, indicating selective advantage in antitumor responses. Phenotype and single-cell gene expression analyses identified dual TCR are predominant during the effective antitumor response, demonstrating selectively increased activation in the TIL compartment and skewing toward an effector memory phenotype. Absence of dual TCR cells impaired immune response to B16F10 but not 6727, suggesting that dual TCR cells may be more influential in responses against poorly immunogenic tumors. Dual TCR cells demonstrated an advantage in recognition of B16F10-derived neoantigens in vitro, providing a mechanistic basis for their antitumor reactivity. Conclusions These results discover an unrecognized role for dual TCR cells in protective immune function and identify these cells and their TCRs as a potential resource for antitumor immunotherapy.
Humanity
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cardiac pericytes mediate the remodeling response to myocardial infarction
Authors: Pearl Quijada, Shuin Park, Peng Zhao, Kamal S.S. Kolluri, David Wong, Kevin D. Shih, Kai Fang, Arash Pezhouman, Lingjun Wang, Ali Daraei, Matthew D. Tran, Elle M. Rathbun, Kimberly N. Burgos Villar, Maria L. Garcia-Hernandez, Thanh T.D. Pham, Charles J. Lowenstein, M. Luisa Iruela-Arispe, S. Thomas Carmichael, Eric M. Small, Reza Ardehali
Journal: Journal of Clinical Investigation (2023)

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-β signaling. Deleting TGF-β receptor 1 in chondroitin sulfate proteoglycan 4–expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac ejection fraction. Furthermore, genetic ablation of Cspg4-expressing cells resulted in excessive vascular permeability, a decline in cardiac function, and increased mortality in the second week after MI. These data reveal an essential role for cardiac pericytes in the control of vascular homeostasis and the fibrotic response after acute ischemic injury, information that will help guide the development of novel strategies to preserve vascular integrity and attenuate pathological cardiac remodeling.
Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy
Authors: Wenzhi Li, Xiaoyu Liao, Kaibo Lin, Renfei Cai, Haiyan Guo, Meng Ma, Yao Wang, Yating Xie, Shaozhen Zhang, Zhiguang Yan, Jiqiang Si, Hongyuan Gao, Leiwen Zhao, Li Chen, Weina Yu, Chen Chen, Yun Wang, Yanping Kuang, Qifeng Lyu
Journal: MedComm (2023)

Abstract The second polar body (PB2) transfer in assisted reproductive technology is regarded as the most promising mitochondrial replacement scheme for preventing the mitochondrial disease inheritance owing to its less mitochondrial carryover and stronger operability. However, the mitochondrial carryover was still detectable in the reconstructed oocyte in conventional second polar body transfer scheme. Moreover, the delayed operating time would increase the second polar body DNA damage. In this study, we established a spindle‐protrusion‐retained second polar body separation technique, which allowed us to perform earlier second polar body transfer to avoid DNA damage accumulation. We could also locate the fusion site after the transfer through the spindle protrusion. Then, we further eliminated the mitochondrial carryover in the reconstructed oocytes through a physically based residue removal method. The results showed that our scheme could produce a nearly normal proportion of normal‐karyotype blastocysts with further reduced mitochondrial carryover, both in mice and humans. Additionally, we also obtained mouse embryonic stem cells and healthy live‐born mice with almost undetectable mitochondrial carryover. These findings indicate that our improvement in the second polar body transfer is conducive to the development and further mitochondria carryover elimination of reconstructed embryos, which provides a valuable choice for future clinical applications of mitochondrial replacement.
Analysis of Plasma Metabolic Profile on Ganglion Cell–Inner Plexiform Layer Thickness With Mortality and Common Diseases
Authors: Shaopeng Yang, Zhuoting Zhu, Yixiong Yuan, Shida Chen, Xianwen Shang, Gabriella Bulloch, Mingguang He, Wei Wang
Journal: JAMA Network Open (2023)

Importance The neural retina is considered a unique window to systemic health, but its biological link with systemic health remains unknown. Objective To investigate the independent associations of retinal ganglion cell–inner plexiform layer thickness (GCIPLT) metabolic profiles with rates of mortality and morbidity of common diseases. Design, Setting, and Participants This cohort study evaluated UK Biobank participants enrolled between 2006 and 2010, and prospectively followed them up for multidisease diagnosis and mortality. Additional participants from the Guangzhou Diabetes Eye Study (GDES) underwent optical coherence tomography scanning and metabolomic profiling and were included for validation. Main Outcomes and Measures Systematic analysis of circulating plasma metabolites to identify GCIPLT metabolic profiles; prospective associations of these profiles with mortality and morbidity of 6 common diseases with their incremental discriminative value and clinical utility. Results Among 93 838 community-based participants (51 182 [54.5%] women), the mean (SD) age was 56.7 (8.1) years and mean (SD) follow-up was 12.3 (0.8) years. Of 249 metabolic metrics, 37 were independently associated with GCIPLT, including 8 positive and 29 negative associations, and most were associated with the rates of future mortality and common diseases. These metabolic profiles significantly improved the models for discriminating type 2 diabetes over clinical indicators (C statistic: 0.862; 95% CI, 0.852-0.872 vs clinical indicators only, 0.803; 95% CI, 0.792-0.814; P &amp;amp;lt; .001), myocardial infarction (0.792; 95% CI, 0.775-0.808 vs 0.768; 95% CI, 0.751-0.786; P &amp;amp;lt; .001), heart failure (0.803; 95% CI, 0.786-0.820 vs 0.790; 95% CI, 0.773-0.807; P &amp;amp;lt; .001), stroke (0.739; 95% CI, 0.714-0.764 vs 0.719; 95% CI, 0.693-0.745; P &amp;amp;lt; .001), all-cause mortality (0.747; 95% CI, 0.734-0.760 vs 0.724; 95% CI, 0.711-0.738; P &amp;amp;lt; .001), and cardiovascular disease mortality (0.790; 95% CI, 0.767-0.812 vs 0.763; 95% CI, 0.739-0.788; P &amp;amp;lt; .001). Additionally, the potential of GCIPLT metabolic profiles for risk stratification of cardiovascular diseases were further confirmed in the GDES cohort using a different metabolomic approach. Conclusions and Relevance In this prospective study of multinational participants, GCIPLT-associated metabolites demonstrated the potential to inform mortality and morbidity risks. Incorporating information on these profiles may facilitate individualized risk stratification for these health outcomes.
Clinical characteristics of heart failure with reduced ejection fraction patients with rare pathogenic variants in dilated cardiomyopathy‐associated genes: A subgroup analysis of the PARADIGM‐HF trial
Authors: Ana Barat, Chien‐Wei Chen, Natasha Patel‐Murray, John J.V. McMurray, Milton Packer, Scott D. Solomon, Akshay S. Desai, Jean L. Rouleau, Michael R. Zile, Zenab Attari, Cong Zhang, Huilei Xu, Nicole Hartman, Claudia Hon, Margaret Healey, William Chutkow, Christopher J. O'Donnell, Jaison Jacob, Marty Lefkowitz, Michael M. Mendelson, Simon Wandel, Denise Yates, Claudio Gimpelewicz
Journal: European Journal of Heart Failure (2023)

To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status.This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj ] = 4 × 10-3 ), leaner (27.8 kg/m2 vs. 29.4 kg/m2 ; padj = 3.2 × 10-3 ), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10-3 ), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10-4 ).Deleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology.
Prevalence, characteristics and cardiovascular and non‐cardiovascular outcomes in patients with heart failure with supra‐normal ejection fraction: Insight from the <scp>JROADHF</scp> study
Authors: Yu Horiuchi, Masahiko Asami, Tomomi Ide, Kazuyuki Yahagi, Kota Komiyama, Hitomi Yuzawa, Jun Tanaka, Jiro Aoki, Shouji Matsushima, Takeshi Tohyama, Nobuyuki Enzan, Hiroyuki Tsutsui, Kengo Tanabe
Journal: European Journal of Heart Failure (2023)
Additional Oncogenic Alterations in<i>RAS</i>-Driven Differentiated Thyroid Cancers Associate with Worse Clinicopathologic Outcomes
Authors: Athanasios Bikas, Sara Ahmadi, Theodora Pappa, Ellen Marqusee, Kristine Wong, Matthew A. Nehs, Nancy L. Cho, Jacob Haase, Gerard M. Doherty, Kartik Sehgal, Justine A. Barletta, Erik K. Alexander, Iñigo Landa
Journal: Clinical Cancer Research (2023)

RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC).We performed a clinical-genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations.Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared to DTCs harboring a solitary RAS mutation, DTC patients with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P<0.001), have larger primary tumors (4.7 vs. 2.5 cm; P=0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P<0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%, P=0.011) when additional mutations were identified.Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision making.